Penile cancer is a disease with a high mortality, serious physical and psychosexual consequences. Our knowledge on the role of Human Papillomavirus (HPV) in penile carcinogenesis has been predominantly derived from studies of mucosal HPV types in the alpha genus (alpha-HPV), one of the 16 genera of HPV. Mucosal alpha-HPV infection is responsible for approximately 50% of annual penile cancer incidence. Little is known about the diversity of HPV types involved in the development of precursor lesions to penile cancer. The significance of cutaneous HPV in the beta-genus (beta-HPV), a group of HPV ubiquitously and persistently present on healthy human skin, or its combined exposures with mucosal alpha-HPV in penile carcinogenesis has not been evaluated. The goal of this project is to conduct a prospective epidemiologic investigation of a new hypothesis: exposures to cutaneous beta-HPV, either individually or jointly with mucosal alpha-HPV, increase the risk of external genital lesions (EGLs) that have malignant potential for penile cancer. The two specific aims of the study are: (1) estimate baseline prevalence of cutaneous beta-HPV and mucosal alpha-HPV exposures, and investigate factors associated with any beta-HPV exposure as well as joint exposures with mucosal alpha-HPV; (2) determine whether baseline exposures to cutaneous beta-HPV, individually or jointly with mucosal alpha-HPV exposures, are associated with subsequent development of EGLs. We propose a case-cohort design nested within an established and ongoing longitudinal cohort of 4072 men (the HIM Study). The study population will consist of a randomly selected sub-cohort of 550 men and all incident EGL cases (n=230 to date) arising from the parent cohort. Baseline serum samples will be tested for type-specific serum antibodies to a wide array of cutaneous beta-HPV and mucosal alpha-HPV types as the marker of HPV exposures using high throughput multiplex serology assays. Incident EGL cases will be enumerated from the parent cohort based on biopsy-confirmed pathologic diagnosis, the gold standard for EGL diagnosis. The proposed project is the first epidemiologic study to evaluate the temporal association between cutaneous beta-HPV infection and risk of EGLs with malignant potential. It utilizes the existing resources of a large NIH-funded study and is a cost-effective strategy to develop testable hypotheses. This study will make a significant contribution by generating early knowledge of the prevalence of cutaneous beta-HPV exposures in the general male community, and the significance of cutaneous beta-HPV in penile carcinogenesis. If cutaneous beta- HPV is found to play an aetiological role in EGLs potentially leading to penile carcinoma, our findings can inform future HPV-related cancer prevention strategies and vaccine development to prevent beta-HPV infection and associated lesions, and in turn reduce penile cancer incidence, especially in older adult men who are at increased risk but lack routine access to the current prophylactic vaccines.